The Ne w E n g l a nd Jo ur n a l o f Me d ic i ne

Medical Progress

TABLE 1. INHERITED AND ACQUIRED CAUSES

OF VENOUS THROMBOSIS.

G ENETIC S USCEPTIBILITY TO V ENOUS

T HROMBOSIS
URI SELIGSOHN, M.D.,

AND

AHARON LUBETSKY, M.D.

HE annual incidence of venous thrombosis,

one of the leading causes of mortality and morbidity, increases from 1 per 100,000 during
childhood to 1 per 100 in old age.1 In this article we
will discuss conditions involving a genetic predisposition to venous thrombosis. The clinical relevance of
this topic has increased with new evidence of the high
prevalence of mutant genes that increase susceptibility
to thrombosis.
Of the three mechanisms of thrombosis defined
by Virchow in the 19th century vessel-wall injury,
stasis, and changes in the composition of blood
(hypercoagulability) the last two predominate in
venous thrombosis. Hypercoagulability can be inherited or acquired (Table 1). The inherited type, which
is also termed inherited thrombophilia, should be
suspected when a patient has recurrent or life-threatening venous thromboembolism, has a family history of venous thrombosis, is younger than 45 years of
age, or has no apparent acquired risk factors, or if
the patient is a woman who has a history of multiple
abortions, stillbirth, or both. Acquired and genetic
causes frequently interact, which makes it difficult to
decide which patients should be tested for inherited
thrombophilia, what tests to perform and when to order them, whether the results of the tests will affect
the duration of anticoagulant therapy, and whether
to examine family members. This review addresses
these and other topics related to hereditary thrombophilia.
HISTORICAL PERSPECTIVE

Antithrombin deficiency and dysfibrinogenemia,

the first inherited thrombophilias to be described,
were found in studies of families in which several
members were affected by venous thrombosis.2,3 Later, heterozygous deficiencies of protein C4 and protein S5 were identified as causes of inherited thrombophilia. Initially, searches for inherited thrombophilias
among patients with idiopathic venous thrombosis
were disappointing, since only 5 to 20 percent of
such patients had inherited thrombophilias.6 The situation changed remarkably in 1993, after the discovFrom the Institute of Thrombosis and Hemostasis and the National Hemophilia Center, Department of Hematology, Chaim Sheba Medical Center, Tel Hashomer, and Sackler Faculty of Medicine, Tel Aviv University, Tel
Aviv both in Israel. Address reprint requests to Dr. Seligsohn at the Institute of Thrombosis and Hemostasis, Chaim Sheba Medical Center, Tel
Hashomer 52621, Israel, or at [email protected].

Inherited
Common
G1691A mutation in the factor V gene (factor V Leiden)
G20210A mutation in the prothrombin (factor II) gene
Homozygous C677T mutation in the methylenetetrahydrofolate
reductase gene
Rare
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Very rare
Dysfibrinogenemia
Homozygous homocystinuria
Probably inherited
Increased levels of factor VIII, factor IX, factor XI, or fibrinogen*
Acquired
Surgery and trauma
Prolonged immobilization
Older age
Cancer
Myeloproliferative disorders
Previous thrombosis
Pregnancy and the puerperium
Use of contraceptives or hormone-replacement therapy
Resistance to activated protein C that is not due to alterations in the factor V gene
Antiphospholipid antibodies
Mild-to-moderate hyperhomocysteinemia
*Levels of factor VIII and fibrinogen may also increase as part of the
acute-phase response.

ery of resistance to activated protein C. This condition

is the most common cause of inherited thrombophilia.7 In most cases it results from the substitution
of adenine for guanine at nucleotide 1691 of the factor V gene (G1691A), which causes the arginine in
residue 506 of the factor V protein to be replaced
by glutamine (Arg506Gln). The resulting protein is
called factor V Leiden.8 In 1996, the substitution of
adenine for guanine at nucleotide 20210 of the prothrombin gene (G20210A) was found to be another
cause of thrombophilia.9 Homocystinuria, a rare type
of thrombophilia, is manifested by both venous and
arterial thrombosis.10 Familial venous thrombosis has
also been associated with the occurrence of two or
more inherited thrombophilias in the same person.11
MECHANISMS OF THROMBOSIS
IN INHERITED THROMBOPHILIA

In most inherited thrombophilias, impaired neutralization of thrombin or a failure to control the generation of thrombin causes thrombosis (Fig. 1). In
these cases, there is a malfunction in a system of natural anticoagulants that maintain the fluidity of the
blood. One such anticoagulant is antithrombin, which,
when bound to heparan sulfate on endothelial cells,
neutralizes the procoagulants thrombin, factor XIa,
factor IXa, and factor Xa. Protein C, another natural
anticoagulant, controls the generation of thrombin.

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MEDICAL PROGRESS

Normal Control of Coagulation

Endothelial-cell/
protein C receptor

Thrombomodulin

Protein C

Activated/
protein C
Protein S

Inactivation of/
activated factor V

Protein S

Inactivation of/
activated factor VIII

Thrombin generation is controlled/

by protein C pathway

Prothrombin

Thrombin is neutralized by/

antithrombinheparan sulfate complex

Thrombin

Coagulation

Coagulation reactions

Mechanisms of Inherited Thrombophilias

Factor V Leiden, G20210A prothrombin/
gene mutation, and deficiencies of/
protein C or protein S lead to decreased/
control of thrombin generation

Prothrombin

Deficiency of antithrombin/
leads to decreased/
neutralization of thrombin

Thrombin

Thrombosis

Coagulation reactions
Figure 1. Major Mechanisms Involved in the Normal Control of Coagulation and Inherited Thrombophilias.
Control of coagulation is achieved by the protein C pathway and antithrombin. In the protein C pathway thrombin bound to thrombomodulin activates protein C, which in turn inactivates activated factor V and factor VIII in the presence of protein S, thereby downregulating the generation of thrombin. The neutralization of thrombin is achieved by antithrombin bound to heparin sulfate. In the
inherited thrombophilias, a deficiency of antithrombin, protein C, or protein S, aberrant activity of factor V, or increased activity of
prothrombin results in decreased neutralization of thrombin or increased generation of thrombin.

The binding of thrombin to thrombomodulin on endothelial cells of small blood vessels neutralizes the
procoagulant activities of thrombin and activates protein C. In large blood vessels, protein C binds to a
specific receptor, and the binding augments the activation of protein C by thrombin. Activated protein
C inactivates factors Va and VIIIa in the presence of
free protein S and phospholipids, thereby inhibiting
the generation of thrombin. Free protein S itself has
anticoagulant effects: it inhibits the prothrombinase
complex (factor Xa, factor Va, and phospholipid),
which converts prothrombin to thrombin, and the
tenase complex (factor IXa, factor VIIIa, and phospholipid), which converts factor X to factor Xa. A decrease in antithrombin activity impairs the neutralization of thrombin, and the reduced activity of protein
C or protein S diminishes the control of thrombin

generation. Both these mechanisms increase susceptibility to venous thrombosis (Fig. 1).
The control of thrombin generation is also compromised by mutations in the gene for factor V or
prothrombin. The Arg506Gln substitution in factor
V Leiden involves the first of three sites on factor Va
that are cleaved by activated protein C. This mutation
slows down the proteolytic inactivation of factor Va,
which in turn leads to the augmented generation of
thrombin.12 Moreover, the mutant factor V has diminished cofactor activity in the inactivation of factor VIIIa by activated protein C.13 Both these abnormalities in factor V cause the in vitro phenomenon
of resistance to activated protein C, resulting in the
failure of activated protein C to prolong the activated
partial-thromboplastin time. For unknown reasons,
the G20210A mutation in the 3' untranslated region

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The Ne w E n g l a nd Jo ur n a l o f Me d ic i ne

of the prothrombin gene is associated with an increased level of plasma prothrombin, an effect that
promotes the generation of thrombin and impairs the
inactivation of factor Va by activated protein C.14,15
The mechanisms by which increased levels of factor
VIII, factor IX, factor XI, fibrinogen, and homocysteine enhance venous thrombosis are unknown.
EPIDEMIOLOGIC AND GENETIC
FEATURES OF INHERITED
THROMBOPHILIA

The frequency of the major inherited thrombophilias varies substantially within healthy populations
and among patients with venous thrombosis. Factor
V Leiden and the G20210A mutation in the prothrombin gene are common among healthy whites
but are extremely rare among Asians and Africans.
Founder effects have been demonstrated for both mutations, suggesting that they occurred after the separation of non-Africans from Africans and after the
divergence of whites and Asians.16,17 The frequency
of all inherited thrombophilias is significantly higher
in unselected consecutive patients with venous thrombosis than in healthy subjects.18-47 This difference is
striking in selected patients with venous thrombosis
who are also likely on clinical grounds to have an inherited thrombophilia (Table 2).
Since factor V Leiden and the G20210A mutation
in the prothrombin gene are relatively common, their
coinheritance with other thrombophilias is not rare.

Four studies that together enrolled 677 members of

families with deficiencies of protein C, protein S, or
antithrombin demonstrated that the prevalence of
venous thrombosis was 13 to 25 percent among subjects with only factor V Leiden, 19 to 57 percent
among subjects with only one of the three deficiencies, and 73 to 92 percent among subjects who coinherited one of the deficiencies and factor V Leiden.48-51 Similar interactions were observed between
factor V Leiden and the G20210A mutation in the
prothrombin gene.52 Hyperhomocysteinemia also interacts with factor V Leiden and the G20210A mutation in the prothrombin gene; the combination of
hyperhomocysteinemia with either factor significantly
increases the risk of venous thrombosis.53,54
Numerous mutations have been described in patients with a deficiency of protein C, protein S, or
antithrombin (Table 3). Type I defects (low activity
and low antigen level) predominate in patients with
a deficiency of protein C or S, whereas both type I
and type II (low activity and normal antigen level) defects are common in patients with antithrombin deficiency. In these three disorders, heterozygotes are
susceptible to venous thrombosis, except for those
with type II antithrombin deficiency involving the
heparin-binding site.55 Homozygous antithrombin deficiency is probably incompatible with life unless it is
a type II defect involving the heparin-binding site,
in which the susceptibility to venous thrombosis is
indistinguishable from that of persons with hetero-

TABLE 2. FREQUENCY OF INHERITED THROMBOPHILIAS AMONG HEALTHY SUBJECTS

AND UNSELECTED AND SELECTED PATIENTS WITH VENOUS THROMBOSIS.

INHERITED THROMBOPHILIA

HEALTHY SUBJECTS

UNSELECTED PATIENTS

SELECTED PATIENTS*

NO.

NO.

NO.

EXAMINED

AFFECTED

EXAMINED

AFFECTED

EXAMINED

AFFECTED

Protein C deficiency

15,070

0.20.4

2008

3.7

767

4.8

Protein S deficiency

2008

2.3

649

4.3

9,669

0.02

2008

1.9

649

4.3

16,150
2,192
11,932
1,811

4.8
0.05
2.7
0.06

1142

18.8

162

40

2884

7.1

551

16

Type I antithrombin
deficiency
Factor V Leiden
G20210A prothrombin
gene mutation

REFERENCES

Miletich et al.,18 Tait et al.,19 Koster et al.,20 Heijboer et

al.,21 Pabinger et al.,22 Tabernero et al.,23 Ben-Tal et
al.,24 Horellou et al.,25 Gladson et al.,26 Melissari et
al.,27 Salomon et al.28
Koster et al.,20 Heijboer et al.,21 Pabinger et al.,22 Tabernero et al.,23 Ben-Tal et al.,24 Gladson et al.,26 Melissari
et al.,27 Salomon et al.28
Heijboer et al.,21 Pabinger et al.,22 Tabernero et al.,23 BenTal et al.,24 Melissari et al.,27 Tait et al.29
Salomon et al.,28 De Stefano et al.30
Poort et al.,9 Salomon et al.,28 Ehrenforth et al.,31 Hillarp
et al.,32 Eichinger et al.,33 Ferraresi et al.,34 Tosetto et
al.,35 Leroyer et al.,36 Souto et al.,37 Alhenc-Gelas et
al.,38 Corral et al.,39 Brown et al.,40 Hainaut et al.,41
Howard et al.,42 Ridker et al.,43 Margaglione et al.,44
Rosendaal et al.,45 Rees et al.,46 De Stefano et al.47

*Nonconsecutive patients who met the following criteria were selected: an age of less than 50 years, a family history of venous thrombosis, a history of
recurrent events, and the absence of acquired risk factors except for pregnancy or the use of oral contraceptives.
All subjects were white.
All subjects were African or Asian (African Americans were excluded).

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MEDICAL PROGRESS

TABLE 3. DIAGNOSTIC TESTS

TEST*

High priority
Increased resistance to activated
protein C

GENETIC BASIS

FOR

TEST RESULT

Factor V Leiden, HR2 haplotype

FOR

THROMBOPHILIAS.

ACQUIRED CONDITIONS

OR

STATES THAT CAN ACCOUNT

FOR

TEST RESULT

Pregnancy, use of oral contraceptives, presence of lupus anticoagulant, use of oral anticoagulant therapy, stroke, increased factor
VIII levels, presence of autoantibodies against activated protein C

Heterozygosity or homozygosity G1691A in exon 10

for factor V Leiden
Heterozygosity or homozygosity G20210A in the untranslated re
for G20210A prothrombin
gion of the gene
gene mutation
Increased level of homocysteine Mutations in the genes for cysta- Deficiencies of folic acid, vitamin B12, or vitamin B6; older age; renal
failure; smoking
thionine b-synthase or methylenetetrahydrofolate reductase
Increased level of factor VIII
Unknown
Stress, exertion, pregnancy, use of oral contraceptives, older age,
acute-phase response
Presence of lupus anticoagulant

Intermediate priority
Decreased protein C activity
161 Different mutations
Liver disease, childhood, use of oral anticoagulants, vitamin K deficiency, disseminated intravascular coagulation, presence of autoantibodies against protein C
Decreased level of free protein S 131 Different mutations
Liver disease, childhood, use of oral anticoagulants, vitamin K defiantigen
ciency, disseminated intravascular coagulation, pregnancy, use of
oral contraceptives, nephrotic syndrome, presence of autoantibodies against protein S
Decreased antithrombin activity 127 Different mutations
Liver disease, use of heparin therapy, disseminated intravascular coagulation, nephrotic syndrome
Increased titer of anticardiolipin

Infectious diseases
antibodies
Low priority
Dysfibrinogenemia (normal or
20 Different mutations
Recent birth, liver disease, disseminated intravascular coagulation
low fibrinogen level and prolonged thrombin time)
Increased level of fibrinogen
Unknown
Acute-phase response, pregnancy, older age, atherosclerosis, smoking
Increased factor IX activity
Unknown

Increased factor XI activity

Unknown

Homozygosity for C677T muta- C677T in exon 4

tion in methylenetetrahydrofolate reductase gene

*Priority for testing is defined in the chart outlined in Figure 2.
A compendium of the point mutations that have been described is available at http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html.
A compendium of the point mutations that have been described is available at http://www.geht.org/pages/database_ang.html.

zygous antithrombin deficiency.56 Persons with a homozygous deficiency of protein C or protein S are
exceedingly rare and present soon after birth with
purpura fulminans or massive venous thrombosis.
Persons who are homozygous for factor V Leiden or
the G20210A mutation in the prothrombin gene are
more common and have a predisposition to venous
thrombosis. The predisposition is greater in homozygotes for factor V Leiden than in heterozygotes.
Factor V Leiden is not the only cause of resistance
to activated protein C. The HR2 haplotype, a unique
and relatively common haplotype of the factor V
gene, causes resistance to activated protein C and increases the risk of venous thrombosis when coinherited with factor V Leiden.57 There is also a rare mutation in the second of the three sites in factor Va that
activated protein C cleaves (Arg306Thr).58 Additional
causes of resistance to activated protein C, probably

genetic but as yet unidentified, also increase the risk

of venous thrombosis.59
Hyperhomocysteinemia, a risk factor for venous
thrombosis,60 can be caused by genetic disorders affecting the trans-sulfuration or remethylation pathways of homocysteine metabolism, or by folic acid
deficiency, vitamin B12 deficiency, vitamin B6 deficiency, renal failure, hypothyroidism, increasing age, and
smoking. A rare example of excessive hyperhomocysteinemia is homozygous homocystinuria due to cystathionine b-synthase deficiency; 50 percent of affected patients present with venous or arterial thrombosis
by the age of 29 years.10 Homozygosity for the C677T
mutation in the methylenetetrahydrofolate reductase
gene is a cause of mild hyperhomocysteinemia in 5 to
15 percent of white and East Asian populations, but
its relation to venous thrombosis is controversial.38
Elevated levels of factor VIII, factor IX, factor XI,

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The Ne w E n g l a nd Jo ur n a l o f Me d ic i ne

or fibrinogen increase the risk of venous thrombosis,

but so far no genetic alterations have been demonstrated in any of these conditions.61-64
CLINICAL FEATURES OF INHERITED
THROMBOPHILIA

Persons with a heterozygous deficiency of protein

C, protein S, or antithrombin and those who are
heterozygous or homozygous for factor V Leiden or
the G20210A mutation in the prothrombin gene typically present with deep-vein thrombosis of the legs,
pulmonary embolism, or both. Less common manifestations are superficial venous thrombosis and thromboses in the cerebral, visceral, and axillary veins. In
more than half the cases, venous thrombosis is provoked by surgery, immobilization, advanced age, pregnancy, or the use of oral contraceptives or hormonereplacement therapy.
In most patients with inherited thrombophilia,
the first thrombotic event occurs before the age of 45
years. The first event is even earlier in patients who
have more than one inherited thrombophilia or who
are homozygous for factor V Leiden or the G20210A
mutation in the prothrombin gene.31,34,48-51,65 Asymptomatic heterozygotes who are relatives of index patients with inherited thrombophilia have a significant
risk of venous thrombosis. The highest risk, 0.87 to
1.6 percent per year, was observed in persons who
were heterozygous for antithrombin deficiency, and
the lowest, 0.25 to 0.45 percent per year, was seen in
persons who were heterozygous for factor V Leiden.
Persons who are heterozygous for the G20210A mutation in the prothrombin gene, protein C deficiency, or protein S deficiency have an annual incidence
of venous thrombosis of 0.55 percent, 0.43 to 0.72
percent, and 0.5 to 1.65 percent, respectively.66-70
RECURRENT VENOUS THROMBOSIS

All patients with venous thrombosis, whether or not

they have a known inherited thrombophilia, are prone
to recurrent thromboses for many years after the first
incident. Recurrence is fatal in approximately 5 percent of patients,71 and in one third of patients, it is
associated with the post-thrombotic syndrome.72 Recurrent venous thrombosis requires prolonged therapy with anticoagulants, which itself carries a significant risk of major hemorrhage. Recurrence is more
common in men, the elderly, patients who are immobilized, patients with cancer, patients who have
had an unprovoked thrombotic event, and patients
who have already had a recurrent thrombosis.72-74 Increased levels of factor VIII and homocysteine also
increase the risk of recurrence.75,76
The effect of inherited thrombophilias on recurrent venous thrombosis has been assessed mainly in
retrospective studies. Recurrent venous thrombosis is
more common in patients with a deficiency of antithrombin, protein C, or protein S77; in those with

more than one inherited thrombophilia52,78; and in

those who are homozygous for factor V Leiden.65
Whether persons who are heterozygous for factor V
Leiden or the G20210A mutation in the prothrombin gene have increased rates of recurrence of venous
thrombosis is controversial.79
INHERITED THROMBOPHILIAS
DURING PREGNANCY AND THE
PUERPERIUM

The predominant sites of thrombosis during pregnancy are the iliofemoral veins and the veins of the
left leg. The risk of venous thrombosis in women with
a deficiency of antithrombin, protein C, or protein S
is substantially increased during pregnancy and the
puerperium. A review of uncontrolled retrospective
studies found that venous thrombosis occurred during pregnancy and the puerperium in up to 60 percent of women with an antithrombin deficiency and
in up to 20 percent of women with a deficiency of
either protein C or protein S.80 A casecontrol study
showed that among 129 asymptomatic female relatives
of patients with a deficiency of antithrombin, protein C, or protein S, those who also had a deficiency
of one of these proteins had a risk of venous thrombosis during pregnancy and the puerperium that was
eight times as high as the risk in those without a deficiency.81 An increased risk of venous thrombosis during pregnancy is also associated with factor V Leiden
(odds ratio, 16.3; 95 percent confidence interval, 4.8
to 54.9) and the G20210A mutation in the prothrombin gene (odds ratio, 10.2; 95 percent confidence interval, 4.0 to 25.9).82 Coinheritance of factor V Leiden
and the G20210A mutation in the prothrombin gene
further increases the risk (estimated odds ratio, 107).83
Inherited thrombophilias also increase the risk of
fetal loss. In a large cohort of women with a deficiency of antithrombin, protein C, or protein S or
factor V Leiden, the odds ratios for fetal loss after
28 weeks of gestation (stillbirth) were 5.2, 2.3, 3.3,
and 2.0, respectively; the odds ratio was 14.3 for women with more than one type of inherited thrombophilia.84 Another study found that the risk of late fetal loss (after 20 weeks of gestation) was tripled in
carriers of the G20210A mutation in the prothrombin gene or factor V Leiden.85 An increased relative
risk of early fetal loss (at less than 25 weeks of gestation) was also observed in women with a deficiency
of protein C, protein S, or antithrombin86 and in carriers of factor V Leiden.87 In a more general case
control study, 52 percent of pregnant women with
fetal growth retardation, preeclampsia, abruptio placentae, or stillbirth were heterozygous for factor V
Leiden or the G20210A mutation in the prothrombin gene or homozygous for the C677T mutation
in the gene for methylenetetrahydrofolate reductase,
as compared with 17 percent of controls.88 These data
provide a rationale for screening women who intend to

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MEDICAL PROGRESS

become pregnant for inherited thrombophilias if they

have a personal or family history of venous thrombosis or if they have three unexplained miscarriages,
abruptio placentae, stillbirth, recurrent fetal growth
retardation, or possibly preeclampsia.
ORAL CONTRACEPTIVES AND
HORMONE-REPLACEMENT THERAPY

The use of oral contraceptives significantly increases the risk of venous thrombosis in a woman with an
inherited thrombophilia. In a study of women using
oral contraceptives, the risk was increased by a factor
of 3.8 in normal women and by a factor of 34.7 in
women who were heterozygous for factor V Leiden.89
Increased risks were also conferred by heterozygosity for the G20210A mutation in the prothrombin
gene, a deficiency of protein C, or a deficiency of protein S90-92; among women with antithrombin deficiency, the incidence of venous thrombosis was 27 percent per year in users of contraceptives, as compared
with 3.4 percent per year in nonusers.92 Among women with factor V Leiden, the risk of venous thrombosis with the use of third-generation contraceptives
is twice that with the use of second-generation contraceptives,93 probably because the third-generation
contraceptives result in a more pronounced resistance
to activated protein C.94
For these reasons, women with inherited thrombophilias should avoid using oral contraceptives, particularly when they have a personal or family history
of venous thrombosis. Screening of healthy women
for thrombophilias, however, is not recommended,
since it would deny contraceptives to about 5 to 10
percent of white women with factor V Leiden or the
G20210A mutation in the prothrombin gene, while
preventing very few fatal venous thromboembolisms.
Screening should be confined to women with a personal or family history of thrombosis.
Hormone-replacement therapy in healthy women
increases the risk of venous thrombosis by a factor
of two to four, but the increased risk probably disappears after one year of treatment.95 A recent study
found that the risk was significantly increased in women with antithrombin deficiency, resistance to activated protein C, or increased levels of factor IX.96 Until
more data are available, it is advisable to search for
inherited thrombophilias only in women with a personal or family history of venous thrombosis and to
avoid hormone-replacement therapy in affected women unless it is strongly indicated.
DIAGNOSIS OF INHERITED
THROMBOPHILIA

With the identification of factor V Leiden and the

G20210A mutation in the prothrombin gene, the
proportion of patients with venous thrombosis in
whom a diagnosis of inherited thrombophilia can be
established has increased. In unselected patients, the

rate has increased from approximately 10 percent to

approximately 30 percent, and in patients with a clinical likelihood of having an inherited thrombophilia,
it has increased from approximately 17 percent to approximately 70 percent. What is the most economical
way of testing for an inherited thrombophilia? Decisions regarding laboratory tests in a given patient can
be made according to a set of priorities (Table 3) and
individualized after the likelihood of inherited thrombophilia is assessed, taking into account that in a few
cases the diagnosis will be missed (Fig. 2). The inclusion of all six high-priority tests in the evaluation (Table 3) should provide the highest diagnostic yield,
because the six conditions being tested for are relatively frequent.75,76,97 Measurement of resistance to
activated protein C in plasma diluted with factor V
deficient plasma is not only highly sensitive and specific for factor V Leiden but is also accurate in patients whose plasma contains lupus anticoagulant or
increased levels of factor VIII and in patients taking
oral anticoagulants. It is also advisable to confirm the
diagnosis of factor V Leiden by a genetic test, because
this information can be used in deciding whether
family members should be examined. In patients with
stroke or with antibodies to activated protein C, resistance to activated protein C can be delineated only
by testing undiluted plasma (Table 3).98,99
Tests of intermediate priority (Table 3) yield positive results less frequently, and low-priority tests only
very rarely diagnose an inherited thrombophilia (e.g.,
dysfibrinogenemia). The association between venous
thrombosis and the C677T mutation in the gene for
methylenetetrahydrofolate reductase or increased levels of fibrinogen, factor IX, or factor XI has not been
definitively established.61-64
The optimal time for performing tests in most patients is six months after the thrombotic event, when
a decision should be made about continuing anticoagulant therapy (Fig. 2). The results of examinations
performed earlier can be misleading, because thrombosis itself can cause low antithrombin levels and elevated levels of factor VIII. At six months, all highpriority tests and a test for antithrombin activity
should be performed in patients who are most likely
to have an inherited thrombophilia. These patients
should then be switched to treatment with low-molecular-weight heparin for two weeks and subsequently
tested for protein C activity and the level of free protein S antigen. If none of these test results are abnormal in a patient with a family history of venous thrombosis or a recurrent thrombosis, it is reasonable to
perform low-priority tests (Table 3). In our algorithm
(Fig. 2), patients likely to have thrombophilia undergo only high-priority tests, but if factor V Leiden,
the G20210A mutation in the prothrombin gene, or
a lupus anticoagulant is detected, intermediate-priority tests should also be performed. Patients with the
least likelihood of having thrombophilia are not tested

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Thrombophilia highly likely in/

a patient with an unprovoked/
thrombotic event who meets/
one of the following criteria:/
/ 45 years/
Age of less than
Recurrent event/
Family history of venous/
thrombosis/
Cerebral- or visceral-vein/
thrombosis/
Stillbirth/
Three or more unexplained/
spontaneous abortions

Thrombophilia likely/
in a patient who meets/
one of the following criteria:/
First unprovoked/ event/
Event provoked by pregnancy/
or the puerperium or the/
use of oral contraceptives or/
hormone-replacement therapy/
Proximal-vein thrombosis,/
pulmonary embolism, or/
both provoked by surgery,/
trauma, or immobilization/
Age of more than 45 years

Thrombophilia unlikely:/
/
Distal-vein thrombosis/
provoked by surgery,/
trauma, or immobilization

Treatment with oral/

anticoagulants for 6 months/
/

Treatment with oral/

anticoagulants for 6 months/
/

Treatment with oral/

anticoagulants for 3 months

Performance of high-priority/
and intermediate-priority/
tests for thrombophilia

Performance of high-priority/
tests for thrombophilia

Therapy should be stopped/

and prophylaxis should be/
initiated if necessary

Therapy should be continued/

indefinitely in patients who meet/
any of the following criteria:/
/ event/
Life-threatening
Cerebral- or visceral-vein/
thrombosis/
Recurrent event/
Antithrombin deficiency/
Homozygosity for factor V/
Leiden/
Combined thrombophilias/
Presence of antiphospholipid/
antibodies

Treatment with oral anticoagulants/

should be continued for an/
additional 6 to 18 months in patients/
who meet any of the following criteria:/
Active cancer//
Continued immobilization/
Venous insufficiency/
Deficiency of protein C or S/
Elevated factor VIII level/
Standard risk of bleeding

Therapy should be stopped unless/

cancer is still active, immobilization/
continues, or severe venous/
insufficiency is present/
Initiation of prophylaxis (use of/
unfractionated or low-molecular-/
weight heparin during high-risk/
situations, such as surgery, trauma,/
immobilization, or air travel for/
more than 4 hours; avoidance of/
oral contraceptives and hormone-/
replacement therapy; maintenance/
of normal homocysteine levels;/
and maintenance of normal weight)

Therapy should be stopped/

if the patient meets any of/
the following criteria:/
/
No thrombophilia/
Heterozygosity for factor V/
Leiden or G20210A/
mutation in the/
prothrombin gene/
High risk of bleeding (as/
indicated by the presence/
of one or more of the/
following: age of more/
than 70 years, history of/
gastrointestinal bleeding,/
history of stroke, renal/
insufficiency, poorly/
controlled anticoagulation,/
and use of antiplatelet/
drugs)

Initiation of prophylaxis/
(use of unfractionated or low-/
molecular-weight heparin/
during high-risk situations,/
such as surgery, trauma,/
immobilization, or air travel/
for more than 4 hours;/
avoidance of oral contraceptives/
and hormone-replacement/
therapy; maintenance of normal/
homocysteine levels; and/
maintenance of normal weight)

Figure 2. Approach to the Diagnosis and Treatment of Thrombophilia in Patients with Venous Thrombosis.
Panel A shows the clinical evaluation of the likelihood of thrombophilia, initial anticoagulant therapy, and the performance of tests.
Panel B shows the criteria for continuing therapy and for prophylaxis.

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MEDICAL PROGRESS

at all; the anticipated recurrence of venous thrombosis in them is low (1.5 percent per year) and does not
outweigh the risk of bleeding due to the prolongation of anticoagulant therapy.100
Before establishing the diagnosis of an inherited
thrombophilia, it is essential to rule out acquired conditions that may produce similar results (Table 3); it
is also advisable to repeat nongenotypic tests with abnormal results. Detection of the same abnormality in
first-degree relatives of the patient provides evidence
of a possible genetic defect.
First-degree relatives of patients with one or more
abnormal test results should be examined to determine whether they should receive primary prophylaxis. A reasonable approach is to test for only the
abnormal factor or factors found in the index patient
when there is no family history of venous thrombosis and to perform all tests of high and intermediate
priority when there is a family history.
THERAPY AND PROPHYLAXIS

Patients with a known or unknown inherited

thrombophilia who present with venous thromboembolism should be treated with a standard regimen
of heparin overlapped with warfarin until an international normalized ratio (INR) of 2.0 to 3.0 is obtained on two consecutive days. This regimen is sufficient for the prevention of skin necrosis, which may
occur during the initiation of warfarin therapy in patients with a deficiency of protein C. The chief goals
of therapy are to prevent recurrent venous thromboembolism, which is fatal in 5 percent of cases.71 Recurrent thromboses also increase the risk of venous
insufficiency72 and impose a need for indefinite anticoagulant therapy, which carries a significant risk of
bleeding. Warfarin therapy reduces the risk of recurrence by 90 to 95 percent, but the annual risk of fatal hemorrhage is 0.25 percent.101 Consequently, the
benefits and hazards associated with increasing the
duration of therapy should be carefully evaluated and
discussed with each patient, with consideration of the
patients preference and clinical and laboratory risk
factors that increase susceptibility to recurrent venous
thrombosis or hemorrhage. Comprehensive, evidencebased guidelines for therapy cannot yet be formulated, but the substantial information reviewed in this
article and our own experience lead us to an algorithm
that applies to all patients with established venous
thrombosis (Fig. 2).
During the initiation of therapy, patients are classified according to their likelihood of having thrombophilia. Patients with the lowest likelihood are treated for three months, and no tests for thrombophilia
are performed. All other patients are treated with warfarin for six months, after which they are examined
for the presence of thrombophilia and assessed for
the risks of recurrence and hemorrhage. On the basis
of this assessment, treatment is discontinued, con-

tinued for 6 to 18 more months, or continued indefinitely.

In patients with hyperhomocysteinemia, we recommend indefinite treatment with folic acid, supplemented by vitamins B6 and B12 if normal levels of homocysteine are not achieved with folic acid alone. Annual
testing of serum vitamin B12 levels is advisable to avoid
potential deleterious effects of folic acid in patients
with vitamin B12 deficiency.
All patients with venous thrombosis of the legs
should wear fitted compression stockings for at least
two years; this measure reduces the incidence of the
post-thrombotic syndrome by 50 percent.102 Other
prophylactic measures for patients who discontinue
therapy are given in Figure 2. Women with an inherited thrombophilia who have had venous thrombosis,
stillbirth, or three unexplained spontaneous abortions
should be treated throughout pregnancy and for six
weeks post partum with low-molecular-weight heparin. Patients with antithrombin deficiency probably
require a more intensive regimen.103
First-degree relatives of index patients who are
asymptomatic but who are affected by a thrombophilia
should be advised of the risk of venous thrombosis.
Primary prophylaxis in these persons includes the administration of low-molecular-weight heparin in highrisk conditions, such as during surgery, trauma, immobilization, and the six-week postpartum period;
maintenance of normal weight and homocysteine levels; and avoidance of contraceptives and hormonereplacement therapy, with the patients preference taken into account. Women with antithrombin deficiency,
combined thrombophilia, or homozygosity for factor
V Leiden or the G20210A mutation in the prothrombin gene should be treated throughout pregnancy and
for six weeks post partum with low-molecular-weight
heparin.
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